Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity.
- Author:
Sun Hong PARK
1
;
Jeong Ah KWAK
;
Sang Hun JUNG
;
Byeongwoo AHN
;
Won Jea CHO
;
Cheong Yong YUN
;
Chang Seon NA
;
Bang Yeon HWANG
;
Jin Tae HONG
;
Sang Bae HAN
;
Youngsoo KIM
Author Information
- Publication Type:Original Article
- MeSH: Adenosine Triphosphate; Animals; Apoptosis; Catalytic Domain; Chalcone; Death, Sudden; Escherichia coli; Hepatocytes; In Vitro Techniques; Inflammation; Liver; Liver Failure, Acute*; Mice; Myeloid Differentiation Factor 88; Phosphotransferases; Plants, Medicinal; Toll-Like Receptors
- From:Experimental & Molecular Medicine 2017;49(11):e392-
- CountryRepublic of Korea
- Language:English
- Abstract: Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock-mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-β-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-κB (NF-κB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-κB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target.
